Hypothesis: Dietary polyphenols can overcome the deleterious effects of hyperglycaemic or inflammatory conditions on the vascular endothelium by modulating endothelial cell metabolism. Results: First, the effects of high-glucose concentrations, inflammatory cytokines and polyphenols on markers of endothelial cell function in HUVECs were explored. Hyperglycaemic conditions did not significantly affect cell proliferation or cell adhesion molecule expression (CAM), whereas TNF-α and IL1-β caused significant increases in cell adhesion molecule expression by HUVECs. Different polyphenols induced different responses, pro- and anti-inflammatory, depending on the concentration and period of exposure. Pre-treatment with the flavonol quercetin significantly reduced CAM expression in HUVECs. Next, the ability of quercetin to overcome the pro-inflammatory effects of hyperglycaemia and cytokine treatments in HUVECs was investigated using a metabolomics approach with a view to understand the effects at a mechanistic level. As a result, significant changes in HUVEC metabolome in response to treatment with high-glucose concentrations or TNF-α have been demonstrated. Increases in lactate concentrations occurred under inflammatory conditions. Further, it was shown that quercetin could shift the lactate concentrations back towards that of the resting cells and also increase inosine concentrations, which is in keeping with an anti-inflammatory action. Quercetin treatments alone were shown to reduce concentrations of the pro-inflammatory metabolites ATP and ADP and, in parallel, increase concentrations of the anti-inflammatory metabolites adenosine and inosine. Subsequently, quercetin metabolites inside the cells and in the culture medium after quercetin treatments were identified, and their effects on the activities of enzymes involved in purine metabolism enzymes were investigated. The inhibition of adenosine deaminase and CD73 activities with physiological cellular concentrations of quercetin was consistent with the elevations observed in adenosine and AMP levels. Conclusions: Quercetin treatments reversed the effects of high-glucose and TNF-α on energy metabolite profiles. Quercetin was shown to enter the cells, and quercetin and its metabolites inhibited enzymes involved in purine metabolism, which is likely the underlying mechanism.